E-Newsletter - July 2019
Spotlight on Alliance Trials
 

Alliance trial lookS to immunotherapy agents Treating Patients with Metastatic Untreated Renal Cell Cancer

Alliance A031704 - PD-Inhibitor (Nivolumab) and Ipilimumab Followed by Nivolumab vs. VEGF TKI Cabozantinib With Nivolumab: A Phase III Trial in Metastatic Untreated Renal Cell Cancer [PDIGREE]

The Alliance trial looks at how well nivolumab and ipilimumab, followed by nivolumab versus cabozantinib and nivolumab, work in treating patients with renal cell cancer that is untreated and has spread to other parts of the body. Immunotherapy with monoclonal antibodies, such as nivolumab and ipilimumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Targeted therapy drugs such as cabozantinib work in different ways to stop blood vessel formation and the process of cancer cell invasion and spread to other organs.

Study Rationale
More than 60,000 people in the United States develop renal cell cancer (RCC) each year. The overall incidence of kidney cancer has been increasing in the U.S., while the mortality rate has decreased recently. Nonetheless, first line management of metastatic renal cell cancer (mRCC) is in flux. Ipilimumab and nivolumab (ipi/nivo) has been accepted as a new standard of care for patients with mRCC. The phase III study (CheckMate 214) showed a benefit in overall survival for patients with intermediate- and poor-risk mRCC treated with ipi/nivo induction followed by every two-week dosing of nivolumab compared against sunitinib as first-line treatment. [1]  In patients who achieve a partial response, stable disease or mixed response, the ipi/nivo induction regimen is followed by nivolumab monotherapy until progression,  most often then followed by a targeted agent against VEGF receptor. In Alliance A031203 (also known as the CABOSUN trial), investigators showed that in first-line treatment of patients with intermediate- and poor-risk mRCC, cabozantinib (an oral, multiple receptor tyrosine kinase inhibitor mainly targeting VEGF receptors and MET) improved median progression-free survival when compared to sunitinib. [2,3] 

Cabozantinib may be immunomodulatory and enhance the immune activation effects of nivolumab. To what extent the addition of cabozantinib could improve the complete response or near complete response rate and/or improve the overall survival for patients treated with ipi/nivo is unknown. That is why Alliance investigators have developed the PDIGREE trial, an open-label, phase III trial of ipi/nivo induction followed by randomization of patients with stable disease or partial responses to either nivolumab or nivolumab and cabozantinib. The primary endpoint of this trial is an improvement in a three-year cumulative overall survival rate, and key secondary endpoints include the one-year complete response rate and progression-free survival. The successful completion of this PDIGREE trial would likely help develop an improved rational post-induction combination treatment for patients with mRCC.

Study Outcomes
The primary, secondary, and exploratory objectives are described below.

Primary objective:
To compare the overall survival (OS) in patients with metastatic renal cell cancer (RCC) treated with ipilimumab-nivolumab followed by either nivolumab versus cabozantinib-nivolumab.

Secondary objectives:

1.   To determine PFS of patients treated with nivolumab versus nivolumab-cabozantinib.

2.   To evaluate the 12-month complete response rate in patients treated with ipilimumab-nivolumab followed by cabozantinib-nivolumab versus ipilimumab-nivolumab followed by nivolumab.

3.   To evaluate the rates of discontinuing therapy at one year.

4.   To compare objective response rates (ORR, assessed by Response Evaluation Criteria in Solid Tumors [RECIST] 1.1 and Immune-Related Response Evaluation Criteria in Solid Tumors [irRECIST] criteria) for patients treated with ipilimumab-nivolumab followed by cabozantinib-nivolumab versus ipilimumab-nivolumab followed by nivolumab.

5.    To document the adverse event profile of ipilimumab-nivolumab followed by cabozantinib-nivolumab.

Key Eligibility Criteria
Some of the eligibility criteria include:

Step 1 Registration Criteria:
-- Histologic documentation of renal cell carcinoma with clear cell component
-- Measurable disease with measurable disease as defined in the protocol
-- Intermediate or poor risk per IMDC criteria
-- CNS Disease allowed, if stable and not otherwise causing symptoms or needing active treatment
-- Karnofsky performance status ≥ 70%
-- Prior Treatment as defined in the protocol
-- Non-pregnant and non-nursing
-- Age ≥ 18 years
-- None of the following:
   –Active autoimmune disease requiring ongoing therapy
   –Ongoing acute toxicity > Grade 2 from previous treatment
   –History of severe allergic, anaphylactic or other hypersensitivity reactions to chimeric or humanized antibodies
   –History of HIV or active hepatitis B/C or tuberculosis
   –Concurrent use of immunosuppressive medication including prednisone above 10 mg daily
   –Uncontrolled adrenal insufficiency
   –Uncontrolled hypertension (systolic BP > 150mmHg or diastolic BP >90mmHg)
   –Major surgery less than 28 days prior to registration
   –Any serious non-healing wound, ulcer, or bone fracture within 28 days prior to registration
   –Any arterial thrombotic events within 180 days prior to registration
   –Clinically significant hematuria, hematemesis, or hemoptysis within 12 weeks prior to registration
   –Cavitating pulmonary lesions or known endotracheal or endobronchial disease manifestations
   –Lesions encasing or invading any major blood vessels
   –Moderate or severe hepatic impairment (child-Pugh B or C)
   –Any history of untreated pulmonary embolism or deep venous thrombosis (DVT) in the 180 days prior to registration
   –Corrected QT interval calculated by the Fridericia formula (QTcF) > 500 ms
   –Unstable cardiac arrhythmia within 6 months prior to registration
   –Any GI bleeding ≤ 180 days, hemoptysis, or other signs of pulmonary hemorrhage ≤ 90 days prior to registration
   –History of abdominal fistula, gastrointestinal perforation, intra-abdominal abscess, bowel obstruction, or gastric outlet obstruction within 180 days prior to registration
   –Active peptic ulcer disease, inflammatory bowel disease, or malabsorption syndrome within 28 days prior to registration
   –Untreated hypothyroidism, evidence of pancreatitis, history of organ transplant, or history of congenital QT syndrome
   –Active treatment with warfarin or any oral factor Xa inhibitors (treatment with LMWH is allowed)
-- Required laboratory values as detailed in protocol/schema in the protocol

Step 2 Registration Criteria:
-- Successful completion of at least one cycle of ipilimumab/nivolumab
-- Resolution of any treatment-related adverse events to grade 1 or less per dose modification section of protocol
-- No more than 56 days from last dose of ipilimumab/nivolumab

Description of Treatment
All patients are treated with up to four cycles of ipi/nivo "induction" treatment.
Patients with progression of disease (PD) after ipi/nivo receive cabozantinib orally (PO) every day on a 28-day cycle until further disease progression or unacceptable toxicity. Patients with complete response (CR) after ipi/ninvo induction receive nivolumab intravenously on day 1 of a 28-day cycle which repeats in the absence of disease progression or unacceptable toxicity.

Patients with stable disease or partial responses after ipi/nivo induction are randomized to one of two groups. Patients in Group 1 receive nivolumab intravenously on day 1 of a 28-day cycle which repeats in the absence of disease progression or unacceptable toxicity. Patients in Group 2 receive nivolumab intravenously on day 1 and cabozantinib orally every day on a 28-day cycle which repeats in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed for up to five years.

Refer to the study protocol, which can be found on the Alliance website at www.AllianceNCTN.org, for complete information on the trial design, treatment plan and patient eligibility.

As of July 30, 2019, eight patients have enrolled to this study. The enrollment target is 698 randomized patients and up to 1,046 patients when accounting for complete responses, progressive disease, and any drop out during induction therapy.

Study chair: Tian Zhang, MD, MHS - Duke University Medical Center
E-mail: tian.zhang2@dm.duke.edu
Activated: 5/9/19
 

References

1. Motzer RJ et al. N Engl J Med. 2018, Epub ahead of print. PMID: 29562145
2  Choueiri TK et al, J Clin Oncol, 2017; 35(6): 591-7. PMID: 28199818
3. Choueiri TK et al, Eur J Cancer, 2018; 94: 115-25. PMID: 29550566

 

 

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